Renal Haemodynamic Effects of B₂ Receptor Agonist Bradykinin and B₂ Receptor Antagonist HOE 140 in Conscious Lambs

Abstract

The present study was designed to test the hypothesis that the high renal vascular resistance characteristic of the newborn results from age-dependent changes in the responsiveness of the renal vasculature to kinins. Two studies were carried out in conscious, chronically instrumented lambs aged 1 and 6 wekks. Firstly, we measured the renal blood flow response to intra-arterial injection of the B, receptor agonist bradykinin over the range of doses 0-800 ng kg". The ED,, renal blood flow response to bradykinin was 50 ng kg-' in both age groups of lambs. Secondly, we measured the effects of intravenous administration of 12.5 pg kg-' of the specific B, receptor antagonist HOE 140; this dose attenuated the renal blood flow response to 50 ng kg" of bradykinin in both age groups. HOE 140 administration was associated with an age-dependent increase in mean arterial pressure, with little effect on heart rate or renal vascular resistance. This study provides new information regarding the effects of kinins in modulating renal haemodynamics during postnatal maturation. We reject our hypothesis and conclude that the high renal vascular resistance of the newborn does not appear to result from age-dependent changes in the responsiveness of the renal vasculature to endogenous kinins.

Age‐Dependent Effects of Captopril on the Arterial Baroreflex Control of Heart Rate in Conscious Lambs

“…This seems unlikely since one would also expect bradykinin and ANG-(1-7) levels to be altered at 6 weeks of age, when the sensitivity of the arterial baroreflex control of HR was not altered by administration of captopril. Also, our previous observations (Patel & Smith, 2000 on the haemodynamic effects of the specific bradykinin B 2 receptor antagonist icabitant do not appear to support the premise that bradykinin modulates the arterial baroreflex control of HR in conscious lambs at 1 week or 6 weeks of age. We measured the haemodynamic effects of circulating bradykinin by administration of icabitant to conscious lambs aged 1 week and 6 weeks (Patel & Smith, 2001.…”

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs

“…From the present observations, it is possible to rule out any involvement of AT 2 receptors alone in modulating systemic and renal hemodynamic effects of ANG II in the immediate postnatal period. Previously, we demonstrated that bradykinin modulates RVR at 6 weeks but not 1 week, postnatally [20,21]. In other studies, we showed that nitric oxide plays a greater role in modulating RVR in lambs aged one as compared to 3 and 6 weeks postnatally [27,28].…”

Cardiovascular effects of peptide kinin B2 receptor antagonists in rats

“…and normotensive rats, although these changes were more pronounced in hypertensive rats (where the B 2 receptor antagonist selectively increased BP and HR). However, in the study of Patel and Smith (2000), icatibant (at about 10 nmol/kg) increased both BP and renal blood flow but not renal vascular resistance. It is nevertheless interesting to point out that both the time course (<15 min) and the extent of hypertension (a few millimetres of mercury) induced by bolus injection of higher doses of icatibant or MEN11270 (0.1-1 µmol/kg) in normotensive conscious rats are very similar to those previously described in hypertensive animals with lower doses of the antagonist (Braun et al 1997).…”

“…The putative role of peripheral B 2 receptors in cardiovascular homeostasis could be exerted through an action at various levels: renal, cardiac, or vascular. Although most studies failed to detect a significant contribution of kinin B 2 receptors in renal vascular resistance (Madeddu et al 1992;Belichard et al 1996;Hoagland et al 1999;Matsumura et al 1999), intrinsic effects of icatibant on renal haemodynamics have been described (Braun et al 1997;Patel and Smith 2000); however, these effects are not necessarily related to changes in BP. Braun et al (1997) (1 µmol/kg).…”

“…For instance, B 2 receptor knockout mice were found to develop an agerelated hypertension in one study but not in others (Rhaleb et al 1999;Milia et al 2001). Likewise, in several studies, selective B 2 receptor antagonists failed to modify cardiovascular parameters (e.g., Wirth et al 1991;Madeddu et al 1992;Belichard et al 1996;Holte et al 1996;Majima et al 1997;Duckacz and Klein 1999;Hoagland et al 1999;Rhaleb et al 2001) and induced a small depressor effect in one study (Toth-Heyn et al 1998) or a small pressor effect in others (Braun et al 1997;Patel and Smith 2000). As previously discussed (Rhaleb et al 2001), these discrepancies could be related to a series of experimental variables including the induction of anaesthesia, the different mammalian species, the genetic background within the same species, the gender and age of the animals, the dose, route, and mode of administration of the antagonist, the experimental design (and consequently the sensitivity of statistical analysis), the time sampling, and the duration of BP monitoring following the antagonist administration.…”